Factors associated with HIV/syphilis co-infection initiating of antiretroviral therapy

ABSTRACT OBJECTIVE To evaluate the prevalence and factors associated with HIV/syphilis co-infection in people initiating antiretroviral therapy in Belo Horizonte, capital of the state of Minas Gerais. METHODS A sectional section of a prospective cohort study was carried out with people living with HIV, treatment-naive, initiating antiretroviral therapy, older than 16 years, and in follow-up treatment at specialized HIV/Aids care services in Belo Horizonte. Sociodemographic, behavioral, clinical, laboratory and pharmacological treatment-related data were obtained through interviews, medical records, and information systems for logistical control of antiretroviral medications and laboratory tests. The dependent variable was the first episode of active syphilis, recorded by the physician in clinical records, within 12 months after beginning of the antiretroviral therapy. Factors associated with HIV/syphilis co-infection were assessed using binary multiple logistic regression. RESULTS Among the 459 individuals included, a prevalence of 19.5% (n = 90) of sexually transmitted infections (STI) was observed, with syphilis (n = 49) being the most frequent STI in these individuals. The prevalence of HIV/syphilis co-infection was 10.6% (n = 49), and the associated independent factors were alcohol use (OR = 2.30; 95%CI: 1.01–5.26), and having a diagnosis of other sexually transmitted infections (OR = 3.33; 95%CI: 1.24–8.95). CONCLUSIONS There was a high prevalence of HIV/syphilis co-infection in people living with HIV initiating antiretroviral therapy in Belo Horizonte. HIV/syphilis co-infection was associated with behavioral and clinical factors, such as alcohol use and diagnosis of other sexually transmitted infections. Prior knowledge about the factors associated with this co-infection may support the decisions of health professionals engaged in the care to people living with HIV, with regard to timely diagnosis, guidance, follow-up and adequate treatment, both for syphilis and HIV.


INTRODUCTION
Sexually transmitted infections (STI) are considered one of the major public health problems in Brazil and worldwide. Their prevention and control entail individual and public benefits, including the decrease in risks of transmission of the human immunodeficiency virus (HIV) 1 .
STIs reach a high rate among sexually active people, and occur silently thus contributing to their dissemination. The syphilis, caused by the etiologic agent Treponema pallidum, and HIV infection 2, 3 have the most common transmission routes, and social determinants.
T. pallidum infection can increase the viral load and decrease the number of TCD4+ lymphocytes, resulting in increased morbidity and mortality in people living with HIV. Moreover, the presence of HIV may affect the transmission of syphilis, its clinical course, response to treatment, and may change its diagnosis 4 . Some Brazilian studies found that factors associated with HIV/syphilis co-infection were age, marital status, male gender, low education, multiple partners, presence of STIs, irregular use of condoms, men who have sex with men (MSM), among others [5][6][7][8][9] . In international studies, the associated factors were male gender, migrants, low education, age, multiple partners, irregular condom use, MSM, illicit drug use, presence of STIs, among others 10-12 . This study aimed to assess the prevalence of HIV/syphilis co-infection in HIV-positive individuals at the beginning of antiretroviral therapy (ART) in Belo Horizonte, Minas Gerais, Brazil, and to identify factors associated with HIV/syphilis co-infection.

METHODS
We carried out a cross-sectional study of a prospective cohort, called Project ECOART "Efetividade da terapia antirretroviral em pessoas vivendo com HIV/tuberculose, HIV/hanseníase ou HIV/leishmaniose visceral no Brasil" (Effectiveness of antiretroviral therapy in people living with HIV/tuberculosis, HIV/leprosy, or HIV/visceral leishmaniasis in Brazil). The project was approved by the research ethics committee of the Universidade Federal de Minas Gerais (protocol CAAE 31192914.3.3001.5124, opinion CEP 769.085) and of the participating services. Research was conducted in compliance with the instructions of Resolution 466/2012 by the National Health Council.
Sample selection was non-randomized, as all eligible individuals were invited to participate in the study. Recruitment occurred between September 2015 and October 2017.
The study was carried out at three specialized care services (Serviços de Assistência Especializada, SAE) in HIV/Aids of the Unified Health System (SUS). SAE I is an outpatient clinic of a state reference hospital for the treatment of infectious diseases and health dermatology; SAE II is a testing and counseling center (Centro de Testagem e Aconselhamento, CTA); SAE III is a reference SAE for the care of infectious and parasitic diseases.
The eligibility criteria were: individuals of both genders, aged 16 years or older, diagnosed with HIV regardless of the time of diagnosis and the clinical condition of the individual, starting ART (from zero to six months of treatment), without previous pharmacological treatment of HIV infection, and who were being followed-up at one of the three selected services. All participants agreed to participate in the study and signed the informed consent form.
The dependent variable was the first episode of active syphilis recorded by the physician in the medical record within 12 months after initiation of ART. The age of individuals was stratified into age groups for descriptive analysis, and as a continuous variable in logistic regression. The variable self-reported color or ethnicity was stratified into white, black, yellow, brown, or indigenous. Marital status was dichotomized into single/divorced/widowed or married/common-law marriage. Education was categorized as up to 9 years, 10 to 12 years, and 13 years or more of formal education for descriptive analysis, and in two categories for logistic regression (up to 9 years, 10 years or more). We also investigated the existence of children, whether or not they have a job, their own income, private health insurance, place of residence, and economic class. In the evaluation of behavioral variables and lifestyle habits, we analyzed the existence of a fixed sexual partner within 12 months after starting ART, alcohol use in the month before the baseline interview, tobacco use at the time of the interview, use of illicit drugs ever in life (marijuana, cocaine, crack, and others, such as ecstasy and glue sniffing), and condom use in the last month and during the last sexual intercourse.
We analyzed the average time of HIV diagnosis by self-report, the initial and final clinical classification of the individual -categorized as A (asymptomatic), B (symptomatic), and C (Aids-defining clinical condition), according to the criteria of the adapted Centers for Disease Control and Prevention (CDC) 13 , the presence of comorbidities, presence of other previous and current STIs, presence of mucous lesions (oral, genital, or anal), viral load, and TCD4 lymphocyte count, according to the Siscel data, mean duration of ART, and treatment regimens, according to the Siclom data. Treatment regimens were categorized as tenofovir/lamivudine/efavirenz (TLE), tenofovir/lamivudine/dolutegravir (TLD), and other (any other antiretroviral regimen). Non-adherence was assessed by self-report, using the question "Have you missed the medication in the last 15 days (yes; no)?" Descriptive analysis was carried out using frequency distribution for categorical variables, and measures of central tendency and variability for continuous variables. Pearson's chi-square or Fischer's exact test was used to compare proportions between categorical variables, and the T-test was used to compare means between continuous variables. The multiple binary logistic regression model was used to assess factors associated with HIV/ syphilis co-infection.
All variables were subjected to collinearity tests. The results of logistic regression were presented by odds ratio (OR), 95% confidence interval (95%CI), and p value. Variables that showed p value of 0.20 or less in the bivariate analysis were included in the multivariate model. The stepwise backward conditional method was used to obtain the final model. The Hosmer-Lemeshow test and the area under the Receiver Operating Characteristics (ROC) curve were used to verify the model fit. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) software, version 22.0, and R Studio, version 4.0.2. All analyses were performed with a 5% significance level.

RESULTS
A total of 459 individuals were enrolled in the study (Figure 1). Among the sociodemographic characteristics of the study general population, it was observed that 81.5% of the individuals were male, with a mean age of 34.7 years (SD = 10.9), and a predominance of the age range of 20 to 34 years (53.4%). Most individuals were single, divorced, or widowed (79.7%), and had 10 years or more of formal education (74.3%). Regarding behavioral characteristics, 27.5% of the individuals used tobacco at the time of the interview, 64.1% used alcohol in any quantity in the month before the interview, 48.1% used illicit drugs at some time in their lives. As for the potential source of HIV infection, more than half (51%) were MSM.
Among the participants, 25.5% reported not using condoms in the last month, and 21.4% in the last sexual intercourse. Clinical classification A (asymptomatic) was observed in 63.4% of individuals at the first visit, and in 80.8% at the last visit. At the beginning of treatment, most participants (88.9%) had detectable viral load and, at the end of 12 months of ART, only 6.8% had detectable viral load. The percentage of missing data was 30.5%. At the beginning of ART, we observed that 26.1% of the individuals had TCD4 lymphocyte counts below 200 cells/mm 3 , and 20.9% started treatment with clinical conditions indicative of Aids. Regarding treatment-related characteristics, the mean time to ART initiation was 78.5 days (SD = 58.97); 63.4% of individuals were using the TDF/3TC/EFV regimen; 14.8% reported non-adherence to treatment; and, 70.8% had been diagnosed with HIV for more than three months (Table 1).
We observed a 19.6% (n = 90) prevalence of STIs registered on the medical record, with more than half of the records being syphilis (n = 49). Among the 41 individuals diagnosed with STIs other than syphilis, we found 9.4% (n = 20) of condyloma and genital warts (anal, vaginal, perianal); 5.6% (n = 12) of genital herpes; 5.6% (n = 12) of hepatitis B and C; and 1.4% (n = 3) of other STIs (gonorrhea/trichomoniasis/unspecified STI). Other oral, anal or genital mucous lesions were also recorded (5%), described as penile ART: antiretroviral therapy.   We also observed 18.4% (n = 9) of other STIs, additionally to the co-infection, being these condyloma and genital warts, hepatitis B and C, and others (gonorrhea/trichomoniasis/ unspecified STIs). It was also observed that 10.2% had some record of lesions in oral, anal or genital mucosa (data not shown in the table).
As shown in Table 1, most co-infected individuals were male (93.9%), aged 20 to 34 years (53.1%), brown or black (71.5%), divorced/single/widowed (85.7%). As for behavioral characteristics, most were MSM (69.4%), had no fixed sexual partner (46.9%), and used alcohol in the month before the baseline interview (73.5%). As for condom use, 26.5% reported not having used in the last month, and 14.3% did not use in the last sexual intercourse. There were differences between the groups with and without co-infection for the variables sex  Table 1).
The characteristics significantly associated with a higher chance of having HIV/syphilis co-infection in the bivariate analysis were male sex, being MSM, and having a diagnosis of other STIs. The characteristics associated with a lower chance of HIV/syphilis co-infection were longer duration of ART, and use of the TLD antiretroviral regimen ( Table 2).
In the multivariate analysis (Table 3), the independent characteristics associated with a higher chance of co-infection were having been diagnosed with other STIs (OR = 3.33; 95%CI: 1.24-8.95), and alcohol use in the month before the interview (OR = 2.30; 95%CI: 1.01-5.26). The variables sex and length of antiretroviral treatment remained in the final model, but did not report statistical significance.

DISCUSSION
People living with HIV (PLHIV) seen in three public specialized HIV care services in Belo Horizonte, who were starting ART, showed high prevalence of STI co-infection (19.6%), with syphilis (10.6%) being the most prevalent. It is noteworthy that the estimated overall prevalence of syphilis among men and women without HIV infection is 0.5% in Brazil 1 . Characteristics independently associated with HIV/syphilis co-infection were diagnosis of other STIs, and use of alcohol in the month prior to the interview.
The prevalence and factors associated with syphilis in PLHIV vary both in Brazilian and international studies. This variation depends on the type of population, such as the key population (transgender, sex workers, people who inject drugs, MSM, and prisoners -and their partners) that have higher prevalence of HIV/syphilis co-infection 14 .
The prevalence of HIV/syphilis co-infection observed in this study was lower than that found in a study conducted in Mkushi, Zambia, in which the authors observed 40.5% HIV/syphilis co-infection in newly diagnosed HIV-positive individuals starting ART 15 . It was also lower than the prevalence found in a prospective multicenter study of MSM in Germany, which was 39.6% 16 . In another study conducted in Brazil with sex workers, the prevalence was 30.8% 17 .
Similar to other studies 18,19 , we also found that having been diagnosed with other STIs was independently associated with a higher chance of HIV/syphilis co-infection.  Another study reviewed the factors associated with HIV/STI co-infection in 295 PLHIV, in which 37% had at least one STI. Among the STIs cited, 32% were syphilis, 16% gonorrhea, and 8% chlamydia. The high prevalence of STIs among PLHIV suggests the need for adequate testing, prevention, and treatment among this population 21 .
In this study, reports of alcohol use prior to the interview were associated with a higher chance of HIV/syphilis co-infection, a result similar to other studies 22,23 . Alcohol consumption is a serious public health problem since it may lead individuals to adopt risky sexual practices and contribute to the lack of STI preventive habits, such as not using condoms, changing partners frequently, and engaging in group or anal sex, leading to increased chances of contracting syphilis and other STIs. This scenario contributes to maintaining the chain of transmission of STIs among PLHIV 24 .
Alcohol is a substance that depresses the central nervous system, and reduces anxiety and inhibition. The belief that using alcohol increases pleasure causes it to be used before or during sexual practices. It is estimated that alcohol consumption among PLHIV is 2.5 times higher than in the remaining population. The use of alcohol and drugs increases up to six times the risk of people with HIV to have unprotected sex and multiple partners. In one study, the prevalence of alcohol abuse among people living with HIV was estimated at 28.6% 25 .
Longer duration of ART was associated with lower chance of HIV/syphilis co-infection, and remained in the final model due to greater robustness, although it did not show statistical significance. It is noteworthy that the results of studies evaluating the association between ART use and STI transmission are controversial.
A retrospective cohort study found an association between the use of ART and a lower chance of HIV/syphilis co-infection at the beginning of treatment, supporting the results found in this study. On the other hand, ART use was associated with higher chance of co-infection in individuals who had syphilis seroconversion during follow-up 26 . In a study by Tsachouridou et al. 27 , individuals taking ART were 2.4 times more likely to have HIV/syphilis co-infection. These studies indicate that the advantages of antiretroviral use are reflected in the sexual behavior of PLHIV of not using condoms. It is likely to be so because feel safe about not transmitting the HIV virus 27 .
In our study, the male sex variable was associated with lower chance of HIV/syphilis co-infection, and remained in the final model due to greater robustness, although it did not show statistical significance. This result was consistent with that of other studies that showed a higher risk of co-infection among males 28,29 .
The prevalence of syphilis and the different STIs found in this study may reflect the inconsistent use of condoms, and other actions to prevent these infections. Awareness about the factors associated with the prevalence of HIV/syphilis co-infection may support the decision-making of professionals involved in the care of PLHIV. The follow-up and adequate treatment of syphilis and STIs require guidance on safe sex practices to prevent these co-infections among the PLHIV.
The limitations of the study concern the use of secondary data with missing elements of general records on clinical information, and laboratory tests of individuals.
The strengths of this study are the quality and processing of primary data collected, with reliability analysis of 10% of the total sample for collection and entry. Of note is the high perfect interdigitated agreement assessed by Kappa statistics, the comprehensive inclusion of explanatory variables, and the robustness of the final model.
The conclusion is that the prevalence of STIs recorded was high, and syphilis was the most prevalent co-infection. Alcohol use and diagnosis of other STIs were associated with a higher chance of HIV/syphilis co-infection among this population.